Programmable pharmaceutical compositions for chrono drug release

Abstract

The present disclosure provides programmable osmotic-controlled oral compositions providing delayed release of a therapeutically acceptable amount of a drug. In certain embodiments, the programmable osmotic-controlled compositions of the disclosure provide a lag time that is independent of the presence or absence of food, type of food, pH, gastric emptying, and volume of gastric fluid. The programmable osmotic-controlled oral compositions of the disclosure comprise a multilayer core comprising a drug for controlled release, wherein the core is coated with a semipermeable membrane comprising an orifice and, optionally, an immediate release coating, comprising a drug for immediate release, over the semipermeable membrane. The multilayered core comprises a pull layer containing the drug and a push layer. The pull layer comprises at least two layers: a placebo layer for providing a desired lag time for the drug release; and an active layer containing the drug and providing a delayed controlled release of the drug. The compositions of the disclosure can be programmed to provide a desired and precise lag time, and release drug, after the lag time, at a rhythm, e.g., that matches the human circadian rhythm of a condition's symptoms and/or of the individual being treated in the application of the therapy to optimize therapeutic outcome and minimize side effects.

What is claimed is: 
     
       1. An osmotic-controlled oral pharmaceutical composition providing delayed release of a therapeutically effective amount of a drug, the composition comprising:
 a) a multilayer core comprising a placebo layer, an active layer, and a push layer, wherein: 
 (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da, or intermediate values thereof, 
 (ii) the active layer comprises at least one drug, and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da, 
 (iii) the push layer comprises at least one osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M Da; and 
 b) a semipermeable membrane, containing at least one orifice and surrounding the core, 
 wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane; the active layer; and the push layer facing away from the at least one orifice, 
 wherein the composition when tested for dissolution in about 900 ml of a dissolution medium comprising about 0.01N HC1, using USP Apparatus II (sinkers) at about 50 rpm and about 37° C., provides a lag time of at least 4 hours during which the composition releases no more than 10% of the drug. 
 
     
     
       2. The composition of  claim 1 , wherein the drug is selected from the group consisting of amphetamines, methylphenidate, diltiazem, carbamazepine, metoprolol, oxprenolol, nifedipine, albuterol, phenylpropanolamine, pseudoephedrine, chlorpheniramine maleate, prazosin, doxazosin, verapamil, oxybutynin chloride, isradipine, hydromorphone, paliperidone, modafinil, armodafinil, liothyronine, oseltamivir (Tamiflu), rifamycin, and glipizide. 
     
     
       3. The composition of  claim 1 , wherein the semipermeable membrane comprises a pH-independent water-insoluble polymer and a water-soluble pore former. 
     
     
       4. The composition of  claim 3 , wherein the pH-independent water-insoluble polymer in the semipermeable membrane is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose triacetate, and combinations thereof. 
     
     
       5. The composition of  claim 3 , wherein the water-soluble pore former is selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, polyvinyl pyrolidone, polyvinyl acetate, mannitol, and methyl cellulose, poloxamer, triethyl citrate, triacetin, hydroxypropyl methylcellulose, glycerol, and combinations thereof. 
     
     
       6. The composition of  claim 3 , wherein the water-soluble pore former is a plasticizer selected from the group consisting of polyethylene glycol, triethyl citrate, triacetin, diethyl tartrate, and combinations thereof. 
     
     
       7. The composition of  claim 3 , wherein the pH-independent water-insoluble polymer and the water-soluble pore former are present in a weight ratio of from about 80:20 to about 99.5:0.5. 
     
     
       8. The composition of  claim 1 , wherein the osmogen in the push layer is selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, lithium sulfate, sodium sulfate, lactose and sucrose combination, lactose and dextrose combination, sucrose, dextrose, mannitol, dibasic sodium phosphate, or combinations thereof. 
     
     
       9. The composition of  claim 1 , wherein the osmogen in the push layer is present in an amount of between about 5 wt% and about 30 wt% of the push layer. 
     
     
       10. The composition  claim 1 , wherein the semipermeable membrane is applied with a coating weight gain of from about 1 wt% to about 50 wt% of the multilayered core. 
     
     
       11. The composition of  claim 1 , wherein the placebo layer is present in an amount of from about 25 wt% to about 40 wt%, based on the total weight of the trilayer core. 
     
     
       12. An osmotic-controlled oral pharmaceutical composition comprising a multilayer core comprising a drug for delayed extended release; a semipermeable membrane containing at least one orifice and surrounding the multilayer core; and an immediate release drug layer containing a drug for immediate release and surrounding the semipermeable membrane, wherein the multilayer core comprises a placebo layer, an active layer, and a push layer, wherein:
 (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da, 
 (ii) the active layer comprises a drug and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da, 
 (iii) the push layer comprises an osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M Da; 
 wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane; the active layer; and the push layer facing away from the at least one orifice, 
 wherein the composition provides an immediate release of the drug present in the immediate release drug layer, and a delayed extended release of the drug present in the multilayer core, and 
 wherein the release of the drug from the multilayer core is delayed by at least 4 hours, during which the composition releases no more than 10% of the drug present in the multilayer core. 
 
     
     
       13. The composition of  claim 12 , wherein the osmogen in the push layer is present in an amount of between about 5 wt% and about 30 wt% of the push layer. 
     
     
       14. The composition of  claim 12 , wherein the semipermeable membrane comprises a pH-independent water-insoluble polymer and a water-soluble pore former at a polymer to pore former ratio of between about 80:20 and about 99.5:0.5. 
     
     
       15. The composition of  claim 12 , wherein the semipermeable membrane is applied with a coating weight gain of from about 1 wt% to about 50 wt% of the multilayered core. 
     
     
       16. The composition of  claim 12 , wherein the placebo layer is present in an amount of from about 25 wt% to about 40 wt%, based on the total weight of the trilayer core. 
     
     
       17. The composition of  claim 12 , wherein the drugs in the immediate release drug layer and in the trilayer core are different. 
     
     
       18. An osmotic-controlled oral pharmaceutical composition providing pulsatile release of a first drug and a second drug, the composition comprising:
 a) a multilayer core comprising layers in the following order: 
 (i) a first placebo layer comprising at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da, 
 (ii) a fist active layer comprising a first drug and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da, 
 (iii) a second placebo layer comprising at least one polyethylene oxide polymer having an average molecular weight from about 300K Da to about 900K Da, 
 (iv) a second active layer comprising a second drug and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da, 
 (v) a push layer comprising an osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M; and 
 b) a semipermeable membrane, containing at least one orifice and surrounding the multilayer core, 
 wherein the layers in the multilayer core are placed in the following order: the first placebo layer in fluid communication with the at least one orifice in the semipermeable membrane; the first active layer; the second placebo layer, the second active layer, and the push layer facing away from the at least one orifice, 
 wherein the pulsatile release comprises release of a first pulse containing the first drug and a second pulse containing the second drug, 
 wherein the release of the first pulse containing the first drug is delayed by at least 4 hours. 
 
     
     
       19. The composition of  claim 18 , wherein the first drug and the second drug are same. 
     
     
       20. The composition of  claim 18 , wherein the first drug and the second drug are different. 
     
     
       21. The composition of  claim 18 , wherein the composition further comprises an immediate release drug layer containing a drug for immediate release and surrounding the semipermeable membrane. 
     
     
       22. A method for making an osmotic controlled pharmaceutical composition, the method comprising:
 (i) preparing a placebo layer blend comprising granules containing at least one polyethylene oxide polymer with an average molecular weight of from about 600K Da to about 900K Da, 
 (ii) preparing an active layer blend comprising granules containing at least one drug and at least one polyethylene oxide polymer with an average molecular weight of less than or equal to about 300K Da, 
 (iii) preparing a push layer blend comprising at least one osmogen and at least one polyethylene oxide polymer with an average molecular weight of greater than or equal to 1M Da, 
 (iv) compressing the placebo layer blend, the active layer blend, and the push layer blend into a trilayer tablet core, 
 (v) coating the trilayer tablet core from step (iv) with a coating solution comprising a water-insoluble polymer and a water-soluble pore former to obtain a coated trilayer core, and 
 (vi) drilling at least one orifice into the coated trilayer from step (v), 
 wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane; the active layer; and the push layer facing away from the at least one orifice, and 
 wherein the composition when tested for dissolution in about 900 ml of a dissolution medium comprising about 0.01N HC1, using USP Apparatus II (sinkers) at about 50 rpm and about 37° C., provides a lag time of at least 4 hours during which the composition releases no more than 10% of the drug. 
 
     
     
       23. A method for treating a condition that requires release of a drug following circadian rhythm of the condition, the method comprising administering to a subject in need thereof an osmotic controlled oral pharmaceutical composition providing delayed release of a therapeutically effective amount of the drug, the composition comprising:
 a) a multilayer core comprising a placebo layer, an active layer, and a push layer, wherein: 
 (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da, or intermediate values thereof, 
 (ii) the active layer comprises the drug, and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da, 
 (iii) the push layer comprises at least one osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M Da; and 
 b) a semipermeable membrane, containing at least one orifice and surrounding the core, 
 wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane; the active layer; and the push layer facing away from the at least one orifice, 
 wherein the composition when tested for dissolution in about 900 ml of a dissolution medium comprising about 0.01N HC1, using USP Apparatus II (sinkers) at about 50 rpm and about 37° C., provides a lag time of at least 4 hours during which the composition releases no more than 10% of the drug. 
 
     
     
       24. The method of  claim 23 , wherein the condition comprises a disease wherein the risks and symptoms of the disease vary predictably over time. 
     
     
       25. The method of  claim 24 , wherein the disease comprises central nervous system (CNS) disorders, asthma, arthritis, congestive heart failure, myocardial infarction, stroke, cancer, peptic ulcer, narcolepsy, epilepsy, migraine, and pain.